DESCRIPTION: This well written clear proposal will test the hypothesis that regulated expression of the PTH/PTHrp receptor is necessary for osteoblast differentiation and bone formation during normal growth. A novel transgenic inducible knockout approach will be taken in mice in aim 1 which will use Cre-lox excision to delete the signal peptide in the PTH/PTHrp receptor in homologous recombinant animals at 12 weeks of age. This model should permit removal of PTH/PTHrp receptor function at any time during mouse development or following additional treatment (ovariectomy), thus avoiding the lethality that occurs when the receptor is inactivated in conventional knockout manner. Development of this new model of PTH/PTHrp receptor function could lead to greater understanding of anabolic function of PTH/PTHrp in bone and tooth development, remodeling, and aging, as well as in growth and metastasis of cancers producing high levels of PTHrp. The mechanistic pathways through which PTH/PTHrp mediate anabolic effects on bone are presently ill defined. The second aim will 1) determine if loss of PTH/PTHrp receptor function affects the differentiation of calvarial osteoblasts and their ability to form a mineralized matrix in culture, and 2) compare the histomorphometric parameters for bone from transgenic and control mice, e.g., tibia and vertebrae.